The antibody response to HIV-1 infection is typically vigorous and sustained but its effectiveness in virus containment in vivo is uncertain. We and others have shown in acutely infected individuals the rapid development of HIV-1 strain-specific neutralizing antibodies (Nab), and the equally rapid emergence of virus escape mutations (Albert et al. (1990) AIDS 4:107-112; Moog et al. (1997) J Virol 71:3734-3741; Wei et al. (2003) Nature 422:307-312; Richman et al. (2003) Proc Natl Acad Sci USA 100:4144-41492). Such strain-specific antibody responses are common, and they clearly drive virus selection in vivo (Wei et al. (2003) Nature 422:307-312; Richman et al. (2003) Proc Natl Acad Sci USA 100:4144-41492). More broadly reactive Nabs develop over longer periods (Pilgrim et al. (1997) J Infect Dis 176:924-932; Montefiori et al. (2001) J Virol 75:10200-10207; Parren et al (1999) Aids 13 Suppl A:S137-162). HIV-1 has evolved a variety of defense mechanisms to avoid antibody recognition, including epitope variation, oligomeric exclusion, conformational masking, glycan cloaking, and steric interference at the virus:cell interface (Kwong et al. (1998) Nature 393:648-659; Wyatt et al. (1998) Nature 393:705-711; Wyatt et al. (1998) Science 280:1884-1888; Kwong et al. (2002) Nature 420:678-682; Labrijn et al. (2003) J Virol 77:10557-10565; Burton et al. (2004) Nat Immunol 5:233-236; Zolla-Pazner et al (2004) Nat Rev Immunol 4:199-210), and together, they contribute to virus persistence in the face of an evolving antibody repertoire (Wei et al (2003) Nature 422:307-312; Richman et al. (2003) Proc Natl Acad Sci USA 100:4144-41492). But the precise nature of this evolving antibody response in vivo is incompletely understood. Analysis of HIV-1 specific monoclonal antibodies has revealed variable loop, CD4 binding site, chemokine co-receptor binding site, surface glycan, and membrane proximal gp41 domains as neutralization targets (reviewed in Burton et al. (2004) Nat Immunol 5:233-236; Zolla-Pazner et al (2004) Nat Rev Immunol 4:199-210), but the prevalence, titers, and breadth of polyclonal antibody responses to these epitopes in humans are generally unknown. This is in part a consequence of technical difficulty in identifying epitope-specific neutralizing antibody responses within a larger context of polyclonal neutralizing and non-neutralizing antibody reactivities (Broliden et al. (1992) Proc Natl Acad Sci USA 89:461-465; Scala et al. (1999) J Immunol 162:6155-6161; Opalka et al. (2004) J Immunol Methods 287:49-65).
It is clear that methods and compositions are needed to identify immunogenic, broadly-cross reactive epitopes on the HIV-1 envelope glycoprotein that might serve as targets of the adaptive humoral immune response in naturally-infected humans. Further needed are methods and compositions that allow for the detection of neutralizing HIV-1 antibodies.